Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2.
Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2.
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DOI：
10.3390/ijms19041264
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发表时间：
2018-04-23
影响因子：
5.6
通讯作者：
Woolard J
中科院分区：
文献类型：
--
作者：
Peach CJ;Mignone VW;Arruda MA;Alcobia DC;Hill SJ;Kilpatrick LE;Woolard J
血管内皮生长因子-A（VEGF-A）是血管生成的关键介质，通过血管内皮生长因子受体（VEGF受体）的IV类酪氨酸激酶受体家族进行信号传导。尽管VEGF-A配体与VEGFR 1和VEGFR 2结合，但它们主要通过VEGFR 2发出信号，导致内皮细胞增殖、存活、迁移和血管通透性。不同的VEGF-A同种型由Vegfa基因在外显子8处的选择性剪接产生，从而产生VEGFxxxa或VEGFxxxb同种型。除了最近鉴定的翻译后通读事件之外，外显子5-7处的选择性剪接事件产生VEGF-A同种型，其生物利用度和与共受体Neuropilin-1的相互作用不同。这篇综述探讨了VEGF-A亚型在VEGFR 2配体结合和下游信号传导方面的分子药理学。为了了解VEGF-A亚型如何具有不同的信号传导，尽管VEGFR 2的亲和力相似，本综述重新评估了这些亚型相对于原型“促血管生成”VEGF 165 a的典型分类。我们还研究了支持VEGF-A亚型信号传导调节的分子机制以及与其他膜和细胞外基质蛋白相互作用的重要性。由于批准的靶向VEGF-A/VEGFR信号传导轴的治疗药物在很大程度上缺乏长期疗效，因此了解这些亚型特异性机制可以帮助未来靶向VEGF受体药理学的药物发现工作。
Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGFxxxa or VEGFxxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF165a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.
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